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Tuesday, April 14, 2015

Biomarker-based asthma phenotypes of corticosteroid response

Inhaled corticosteroids (ICSs) are the mainstay of treatment of asthma. However, a considerable proportion of asthmatic patients do not respond to ICSs based on lung function, or other clinical outcomes, or both. Therefore, biomarkers relevant to the underlying pathophysiologic process, the response to treatment, or both would be useful in personalizing care of asthmatic patients. This need led Cowan et al to follow up from an original study of a 2 phase trial consisting of a steroid-naïve phase 1 and a 28-day trial of ICSs (phase 2) during which fraction of exhaled nitric oxide (FENO) values, eosinophil counts, and urinary bromotyrosine (BrTyr) levels were measured in asthmatic patients (J Allergy Clin Immunol 2015; 135(4): 877-883).

Over the last decade, FENO values and sputum eosinophil counts have been used as biomarkers of airway inflammation and predictors of steroid responsiveness. FENO values are correlated with airway eosinophilia and associated with airway hyper-responsiveness. Moreover, studies indicate that high FENO values in asthmatic patients indicate an at-risk phenotype for exacerbations and predict clinical response to ICSs or oral corticosteroids. Eosinophils are well recognized as biomarkers of active atopic inflammation and a relationship exists between sputum eosinophil counts and exacerbation of withdrawal of steroids. Upon activation, eosinophils undergo respiratory burst, generating high levels of reactive oxygen species and eosinophil peroxidase that is unique in its ability to convert respiratory burst-generated hydrogen peroxide into hypobromous acid, a reactive brominating oxidant that modifies protein tyrosine residues forming urinary BrTyr.

The authors compared the utility of a panel of biomarkers consisting of FENO, sputum eosinophils, and urine BrTyr that identify the presence of atopic inflammation and oxidative stress for prediction of clinical response to steroids. They show that the effect of ICSs on inflammatory biomarkers was not uniformly concordant, although there were substantial parallel decreases among biomarkers. Each of the biomarkers had utility for predicting steroid responsiveness; the combination of high FENO values and high urinary BrTyr levels had particular power to predict a favorable clinical response to ICS therapy with either improvement in Asthma Control Questionnaire score, FEV1 or airway reactivity. Cowan concludes that future studies must focus on evaluation of biomarker panels for assessment of exacerbation risk and whether the magnitude of change in biomarker values might predict the magnitude of clinical benefit with treatments.

Question for the authors:
Do you see other applications for this biomarker panel for the clinical benefit of asthma, such as aiding in the determination of asthma subtypes early in diagnosis?

Response from the authors:

Our study highlights the potential for utilizing the combination of urinary Br Tyr and FENO to predict the likelihood of steroid responsiveness in asthmatic individuals, without resorting to sputum induction, preparation and analysis.  These measurements could be made at the first clinic visit so that treatment can be tailored to the individual allowing steroids to be prescribed in a targeted fashion whilst also allowing the earlier consideration of other treatments in non-steroid responsive asthma subtypes.  Further studies should focus on the identification of alternative treatments in these steroid-unresponsive phenotypes.

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